Amyloids as Sensors and Protectors (ASAP) Hypothesis

Abstract

This paper propounds the Amyloids as Sensors and Protectors (ASAP) hypothesis. In this novel hypothesis, we provide evidence that amyloids are capable of sensing dysfunction, and after misfolding, initiate protective cellular responses. Amyloid proteins are initially protective, but chronic stress and overstimulation of the amyloid sensor leads to pathology. This proposed ASAP hypothesis has two sequential stages: (i) sensing, and then (ii) protection. Sensing involves a conformational change of amyloids in response to the cellular environment. The protection aspect translates conformational change into a cellular response via several mechanisms. The most obvious mechanism is that protein misfolding triggers the protective unfolded protein response, and thus downregulates protein translation and increases chaperone proteins. Other documented responses include metabolic pathways and microRNAs. This ASAP hypothesis has precedence, as amyloid sensors exist (evidenced by CPEB and Sup35), and both prion and amyloid-β sensing redox stress and metals. Our hypothesis expands on previous observations to link sensing with inciting protective cellular response. Furthermore, we substantiate the ASAP hypothesis with previously published evidence from several amyloid diseases. This novel hypothesis links disparate findings in amyloid diseases: metabolic dysfunction, unfolding protein response/chaperones, modification of amyloids, and nutrient or caloric sensing. While this hypothesis can be applied to Alzheimer's disease, it goes beyond the Alzheimer's context. Thus all amyloid proteins can potentially act as sensors of misfolding-causing stress. Finally, this hypothesis will allow for the sensor mechanism and metabolic dysfunction to serve as biomarkers of the diseases as well as therapeutic targets early in disease pathology.

DES-Amyloidoses “Amyloidoses through the looking-glass”: A knowledgebase developed for exploring and linking information related to human amyloid-related diseases

“…The idea that the amyloids present a system is not new [ 112 – 114 ]. The reason is that they have networks that suggest interrelations with other biological networks and environmental stressors that can induce metabolic changes that may impair homeostatic defenses during the lifetime of humans.…”

“…The reason is that sensitivity towards environmental pathogens (e.g., pesticides), reactive oxygen species, or metals characterizes amyloid aggregation, which partially explains the idiopathic amyloid disorders, is more frequent than familial cases. Fig 1 suggests that IAPP being more prone to Aβ Amyloidosis than AA amyloidosis may be a consequence of the divergence in its interaction with the NLRP3-inflammasome that can sense and respond to dysfunction triggered by environmental stressors [ 114 ].…”

Alzheimer’s disease as a syndrome of overloaded amyloidic synaptic tagging in memory networks

“…This is not to say that the hypothesis is free of issues. For instance, some have suggested Aβ accumulation is not the cause of AD, particularly LOAD, but a response Panza et al, 2019b;Petrofes Chapa et al, 2012;Struble et al, 2010). Issues include inconsistencies between the spatiotemporal deposition of Aβ and the progress of cognitive symptoms, criticisms of preclinical experimental approaches and ambiguity over the exact toxic species of Aβ.…”